The production of insulin is central to the regulation of carbohydrate and lipid metabolism. Insulin imbalances lead to conditions such as type II diabetes mellitus, a serious metabolic disease that currently afflicts approximately 246 million people worldwide, and is expected to affect 380 million by 2025. Insulin is secreted from pancreatic beta-cells in response to elevated plasma glucose which is augmented by the presence of fatty acids. The recent recognition of the function of the G-protein coupled receptor GPR40 in modulating insulin secretion has provided insight into regulation of carbohydrate and lipid metabolism in vertebrates, and further provided targets for the development of therapeutic agents for disorders such as obesity, diabetes, cardiovascular disease and dyslipidemia.
GPR40 is a member of the gene superfamily of G-protein coupled receptors (GPCRs) or 7-transmembrane receptors (7TM receptors). These receptors are membrane proteins characterized as having seven transmembrane domains, and respond to a variety of molecules by activating intra-cellular signalling pathways critical to a diversity of physiological functions.
At present there is no cure for diabetes, but the disease can often be managed satisfactory, and various treatments are used to ameliorate the disease. For example, dietetic measures have been employed to balance the relative amounts of proteins, fats, and carbohydrates in a patient. Diabetes education and awareness programmes have also been implemented in several countries. In addition, diabetic conditions of moderate or severe intensity are treated by the administration of insulin. Also, prescription drugs such as thiazolinediones have been employed to rejuvenate impaired insulin production in adult onset diabetics. Other drugs are used to modulate the effectiveness of insulin. In any case, treatment of either juvenile or adult onset diabetes, has achieved only partial success. This is due to most agents targeting either improved beta-cell function or reducing insulin resistance, with the effect attenuating as the disease progressively worsens. Thus patients require the use (often daily) of a combination of agents to control the disease.
Biguanides, such as metformin, became available for treatment of type 2 diabetes in the late 1950s, and have been effective hypoglycaemic agents ever since (Vigneri and Goldfine (1987) Diabetes Care 10, 118-122). Little is known about the exact molecular mechanism of these agents. As an insulin sensitizer, metformin acts predominantly on the liver, where it suppresses glucose release (Goldfine (2001) Hospital Practice 36, 26-36). Metformin has also been shown to inhibit the enzymatic activity of complex I of the respiratory chain and thereby impairs both mitochondrial function and cell respiration, and in so doing decreasing the ATP/ADP ratio which activates AMP-activated protein kinase (AMPK), causing catabolic responses on the short term and insulin sensitization on the long term (Brunmair et al. (2004) Diabetes 53, 1052-1059; Tiikkainen et al. (2004) Diabetes 53, 2169-2176). This drug has been proven effective in both monotherapy and in combination with sulfonylureas or insulin (Davidson and Peters (1997) American Journal of Medicin 102, 99-110). Diabetes in the young is a global phenomenon that is increasing in incidence. Some key transcription factors, important for beta-cell development, differentiation and function, are implicated in diabetes in the young. Some of these are direct targets of current therapeutic agents. The cost of current diabetic drugs is very high and the development of more affordable alternative therapies would be an advantage. The global burden of type 2 diabetes is huge, and action is required to endure affordable diabetes treatment to improve the quality of life of those individuals affected.
As a result of its adipogenic effect, insulin has the undesirable effect of promoting obesity in patients with type 2 diabetes. (Moller, D. E. (2001) Nature 414:821-827). Unfortunately, other anti-diabetic drugs, including metformin, which are currently being used to stimulate glucose transport in patients with type 2 diabetes also possess adipogenic activity. Thus while current drug therapy may provide reduction in blood sugar, it often promotes obesity. Accordingly, new compositions and methods for treating hyperglycemia are desirable. Compositions that stimulate glucose uptake without generating concomitant adipogenic side effects and with no risk of causing excess insulin secretion and concequential hypoglycaemia are especially desirable.
The seven-transmembrane receptor GPR40, or free fatty acid receptor 1 (FFA1/FFAR1), was recently found to be highly expressed on pancreatic beta-cells, and activated by physiological concentrations of free fatty acids. Activation of GPR40 enhanced glucose-stimulated insulin secretion (GSIS), but did not affect insulin secretion at low glucose concentrations. The enhancement of GSIS by GPR40 has been confirmed in vivo. Furthermore, two single nucleotide polymorphisms of GPR40 significantly correlating to obesity and impaired insulin secretion, further validating the link between the receptor and the disease.
WO08030618A1 (BENZO-FUSED COMPOUNDS FOR USE IN TREATING METABOLIC DISORDERS) discloses compositions for treating metabolic disorders such as type II diabetes. This document specifically relates to compounds capable of modulating GPR40.
WO05086661A2 (COMPOUNDS, PHARMACEUTICAL COMPOSITIONS AND METHODS FOR USE IN TREATING METABOLIC DISORDERS) describes alkynyl containing compounds capable of modulating the G-protein-coupled receptor GPR40, compositions comprising the compounds, and methods for their use for controlling insulin levels in viva and for the treatment of conditions such as type II diabetes.
WO08001931A2 (FUSED CYCLIC COMPOUNDS) describes novel fused cyclic compounds having a GPR40 receptor function modulating action, and which are useful as insulin secretagogues or agents for the prophylaxis or treatment of diabetes and the like.
US20080021069A1 (Receptor Function Regulating Agent) also relates to a GPR40 receptor function regulator comprising a fused imidazole compound. According to the specification the GPR40 receptor function regulator is useful as an agent for the prophylaxis or treatment of obesity, hyperinsulinemia, type 2 diabetes and the like.
WO08054675A2 (ANTIDIABETIC BICYCLIC COMPOUNDS) focuses on a new class of GPR40 agonists. The compounds are useful in the treatment of diseases that are modulated by GPR40 agonists, including type 2 diabetes and hyperglycemia that may be associated with type 2 diabetes or pre-diabetic insulin resistance.
WO05051890A1 (AMINOPHENYLCYCLOPROPYL CARBOXYLIC ACIDS AND DERIVATIVES AS AGONISTS TO GPR40) discloses novel therapeutic compounds for use as GPR40 agonists.
Winzell and Ahrén (G-protein-coupled receptors and islet function—Implications for treatment of type 2 diabetes—Pharmacology & Therapeutics 116 (2007) 437-448) confirm that many efforts have been made to produce small molecule GPR40 receptor agonists and antagonists to investigate their potential as drugs for type 2 diabetes. It is mentioned that in clonal β cells, insulin secretion could be potentiated by addition of a GPR40 agonist, suggesting that acute activation of GPR40 may be useful to stimulate insulin secretion. However, since the mouse model with transgenic over-expression of GPR40 exhibited impaired β-cell function and type 2 diabetes chronic activation of the receptor may cause deleterious effects. Therefore, the authors suggest that a GPR40 antagonist may be a more efficient concept because patients with type 2 diabetes usually have elevated circulating free fatty acids.
Briscoe et al (Pharmacological regulation of insulin secretion in MIN6 cells through the fatty acid receptor GPR40: identification of agonist and antagonist small molecules—British Journal of Pharmacology (2006) 148, 619-628) disclose the pharmacology of a novel small-molecule agonist of GPR40 together with a selective antagonist of GPR40. Using these compounds, the authors verify that the potentiation of insulin secretion by fatty acids appears to be mediated at least partially through GPR40, and that GPR40 agonists can function as glucose-sensitive secretagogues in vitro.
Garrido et al. (Synthesis and activity of small molecule GPR40 agonists—Bioorganic & Medicinal Chemistry Letters (2006) 16, 1840-1845) and McKeown et al (Solid phase synthesis and SAR of small molecule agonists for the GPR40 receptor—Bioorganic & Medicinal Chemistry Letters (2007) 17, 1584-1589) focus on small molecule GPR40 receptor agonists and antagonists to investigate their potential as drugs for type 2 diabetes. The data gathered in the present work suggest that a small molecule GPR40 ligand could help regulate insulin secretion and as such present GPR40 as a potential target for Type II Diabetes.
Tan et al. (Selective small-molecule agonists of G protein-coupled receptor 40 promote glucose-dependent insulin secretion and reduce blood glucose in mice—Diabetes (2008) 57, 2211-2219) studied three new selective GPR40 agonists in wild-type and GPR40 knock-out mice in acute and chronic studies, and concluded that GPR40 does not mediate the chronic toxic effect of free fatty acids on pancreatic islet function, but potentiate GSIS after both acute and chronic administration, and may therefore be of potential benefit for control of type 2 diabetes also in humans.
However, none of the documents disclose the compounds of the present invention.